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2024

J Med Chem. 2024 Aug 22;67(16):14493-14523. doi: 10.1021/acs.jmedchem.4c01241. Epub 2024 Aug 12.

Property and Activity Refinement of Dihydroquinazolinone-3-carboxamides as Orally Efficacious Antimalarials that Target PfATP4

Trent D Ashton, Petar P S Calic, Madeline G Dans, Zi Kang Ooi, Qingmiao Zhou, Josephine Palandri, Katie Loi, Kate E Jarman, Deyun Qiu, Adele M Lehane, Bikash Chandra Maity, Nirupam De, Carlo Giannangelo, Christopher A MacRaild, Darren J Creek, Emma Y Mao, Maria R Gancheva, Danny W Wilson, Mrittika Chowdury, Tania F de Koning-Ward, Mufuliat T Famodimu, Michael J Delves, Harry Pollard, Colin J Sutherland, Delphine Baud, Stephen Brand, Paul F Jackson, Alan F Cowman, Brad E Sleebs.

The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia. Research School of Biology, Australian National University, Canberra 2601, Australia. TCG Lifesciences, Kolkata, West Bengal 700091, India. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide 5005, Australia. School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia. Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria 3216, Australia. Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K. MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, Geneva 1215, Switzerland. Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC, La Jolla, California 92121, United States.

Service type: Stock strains

Abstract

To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound S-WJM992, were shown to inhibit PfATP4-associated Na+-ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, S-WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.

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